Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12.
Tester W, Porter A, Asbell S, Coughlin C, Int J Radiat Oncol Biol Phys; 25(5):783-90 1993
PURPOSE: This Phase II study was designed to test the tolerance and effectiveness of concurrent cisplatin-radiotherapy in the treatment of invasive bladder cancer. Objectives were to determine toxicity, complete response rate, bladder preservation rate, and survival. METHODS AND MATERIALS: Patients with invasive bladder cancer, clinical Stages T2-4, NO-2 or NX, MO were treated with pelvic radiotherapy 40 Gy in 4 weeks and cisplatin 100 mg/m2 on days 1 and 22. Complete responders were given an additional 24 Gy bladder boost plus a third dose of cisplatin; patients with residual tumor after 40 Gy were assigned radical cystectomy. RESULTS: The complete remission rate following cisplatin and 40 Gy for evaluable cases was 31/47 (66%). Acute toxicity was acceptable with only two patients not completing induction therapy. Patients with poorly differentiated tumors were more likely to achieve complete remission. Of fully evaluable patients, 28/42 (67%) achieved complete remission with induction therapy, 11 remain continuously in remission, and eight have relapsed with bladder as the only site of failure. Five of these eight cases relapsed with noninvasive tumor. Of the 14 patients who failed to achieve complete remission, only three remain disease-free. Median survival is not reached, with 17/42 (19/48) deaths reported. Actuarial survival is 64% at 3 years. CONCLUSION: This combined cisplatin-radiotherapy regimen was moderately well-tolerated and associated with tumor clearance in 66% of patients treated. Isolated bladder recurrences with invasive carcinoma are infrequent. Better definition of pretreatment selection criteria is needed if combined modality treatment is to achieve disease control and organ preservation for patients with bladder cancer.

Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03.
Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM,  J Clin Oncol; 16(11):3576-83 1998
PURPOSE: To assess the efficacy of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy in patients with muscle-invading bladder cancer treated with selective bladder preservation. PATIENTS AND METHODS: One hundred twenty-three eligible patients with tumor, node, metastasis system clinical stage T2 to T4aNXMO bladder cancer were randomized to receive (arm 1, n=61 ) two cycles of MCV before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart. Patients assigned to arm 2 (n=62) did not receive MCV before concurrent cisplatin and radiation therapy. Tumor response was scored as a clinical complete response (CR) when the cystoscopic tumor-site biopsy and urine cytology results were negative. The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and one additional dose of cisplatin. Those with less than a CR underwent cystectomy. The median follow-up of all patients who survived is 60 months. RESULTS: Seventy-four percent of the patients completed the protocol with, at most, minor deviations; 67% on arm 1 and 81% on arm 2. The actuarial 5-year overall survival rate was 49%; 48% in arm 1 and 49% in arm 2. Thirty-five percent of the patients had evidence of distant metastases at 5 years; 33% in arm 1 and 39% in arm 2. The 5-year survival rate with a functioning bladder was 38%, 36% in arm 1 and 40% in arm 2. None of these differences are statistically significant. CONCLUSION: Two cycles of MCV neoadjuvant chemotherapy were not shown to increase the rate of CR over that achieved with our standard induction therapy or to increase freedom from metastatic disease. There was no impact on 5-year overall survival.

Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group.
Coppin CM, Gospodarowicz MK, James K, Tannock IF, J Clin Oncol; 14(11):2901-7 1996
A prospective randomized trial was conducted to determine whether the addition of concurrent cisplatin to preoperative or definitive radiation therapy in patients with muscle-invasive bladder cancer improved local control or survival. PATIENTS AND METHODS: Ninety-nine eligible patients with T2 to T4b transitional cell bladder cancer participated, 64% with cT3b or cT4. Patients and their physicians selected either definitive radiotherapy or precystectomy radiotherapy; patients were then randomly allocated to receive intravenous cisplatin 100 mg/m2 at 2-week intervals for three cycles concurrent with pelvic radiation, or to receive radiation without chemotherapy. Patients were stratified by clinical tumor stage and by radiation plan. The median follow-up duration is 6.5 years. RESULTS: The occurrence of distant metastases was the same in both study arms. However, 25 of 48 control patients have had a first recurrence in the pelvis, compared with 15 of 51 cisplatin-treated patients (P = .036). The pelvic relapse rate in the two groups was significantly reduced by concurrent cisplatin (P = .038, log-rank test) and this effect was preserved in a stepwise Cox regression model of prognostic factors (hazards ratio, 0.50; 90% confidence interval [CI], 0.29 to 0.86; P = .036). The hazard reduction was similar for both radiation plans. Pretreatment leukocytosis and high clinical stage were independent adverse factors in a Cox model of overall survival, but the effect of cisplatin was not significant. CONCLUSION: Concurrent cisplatin may improve pelvic control of locally advanced bladder cancer with preoperative or definitive radiation, but has not been shown to improve overall survival. The use of concurrent cisplatin had no detectable effect on distant metastases.

Acta Oncol 1994;33(5):561-5

Radical external beam radiotherapy of urinary bladder carcinoma. An analysis of results in 500 patients.

Skolyszewski Between 1970 and 1985, 500 patients with urinary bladder carcinoma received external beam radiotherapy with curative intent at the Centre of Oncology in Krakow. The 5-year survival without evidence of cancer for T1 patients was 100% (5/5), for T2 48.7% (19/39), for T3 32% (128/400), and for T4 7.1% (4/56).

Clin Oncol (R Coll Radiol) 1991 May;3(3):155-61

Bladder cancer: long-term follow-up results of patients treated with radical radiation.

Gospodarowicz . We present a retrospective review of the Princess Margaret Hospital experience in treating transitional cell carcinoma of the bladder and emphasis on the long-term follow-up of patients treated with radiotherapy (XRT). Between 1972 and 1980, 355 patients were treated with a radical course of external beam radiation. The overall survival was 20% at 10 years and the cause-specific survival was 32%. Radiation treatment resulted in a long-term bladder preservation in at least 25% of patients. The majority of long-term survivors without evidence of relapse were patients with T1 (solitary tumours), T2 and T3a tumours.

J Urol 1989 Dec;142(6):1448-53; discussion 1453-4

Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis.

Gospodarowicz. Data on 121 consecutive patients treated with radical radiation between 1981 and 1985 are presented. Over-all actuarial survival of the patient population (median age 70 years) was 31.6% at 5 years and cause-specific survival was 44.8%. At analysis 33 of 121 patients (27.3%) were alive with preserved bladder function. I

Radiother Oncol 1991 Oct;22(2):111-7

Bladder carcinoma--a 20-year review of radical irradiation therapy.

Jahnson . Between 1967 and 1986, 319 patients, judged unsuitable for cystectomy, were scheduled to receive curative radiation treatment for transitional cell cancer of the urinary bladder. Crude and corrected 5-year survival for all stages were 18% and 28%, respectively. Corrected 5-year survival by stage was: T1-57%, T2-31%, T3-16% and T4-6%. Fifty-seven patients (18%) never completed the scheduled treatment and all but two of them died in a short time from tumour progression. Local response could be evaluated in 179 of the 262 patients, who completed the radiation treatment. In 130 patients (73%) complete local response was observed and 49 patients (27%) had persistent tumour. Corrected 5-year survival in the responder group was 53% compared to 8% in the non-responder group. Intestinal complications occurred in 51 patients, of whom 24 were operated upon and another four died before operation from radiation-induced intestinal complications. More than 80% of all intestinal and/or urinary tract complications were observed within 3 years after irradiation.

Acta Oncol 1990;29(7):909-14

External beam radiation treatment of urinary bladder carcinoma. An analysis of results in 203 patients.

Salminen. In a retrospective study, 203 patients with cancer of the urinary bladder were analysed concerning treatment outcome, survival and some prognostic factors. Radiotherapy with curative intent and a tumour dose of 66 Gy in 9 weeks with a 3 weeks' pause after 33 Gy was the planned treatment for 155 patients. Preoperative radiotherapy with a tumour dose of 40 Gy in 4 weeks was delivered to 28 patients, 4-6 weeks prior to cystectomy. Twenty patients with advanced disease received palliative radiotherapy with a tumour dose of 30 Gy in 2 weeks. A significant initial response to radiotherapy was obtained in 26.7% of the patients. The actuarial 5-year survival was 24% for patients treated with definitive radiotherapy only.

Int J Radiat Oncol Biol Phys 1999 Dec 1;45(5):1239-45

A population-based study of the use and outcome of radical radiotherapy for invasive bladder cancer.

Hayter From the 20,906 new cases of bladder cancer diagnosed in Ontario from 1982 to 1994, we identified 1,372 cases treated by radical radiotherapy (78% male, 22% female; mean age 69.8 years). The median interval to start of radical RT from diagnosis was 13.4 weeks. Ninety-three percent of patients were treated on high-energy linacs, and the most common dose/fractionation scheme was 60 Gy/30 (31% of cases). Five-year survival rates were as follows: bladder cancer cause-specific, 41%; overall, 28%; cystectomy-free, 25%; bladder cancer cause-specific following salvage cystectomy, 36%; overall following salvage cystectomy, 28%. Factors associated with a higher risk of death and a poorer cystectomy-free survival were histology (squamous or nonpapillary transitional cell carcinoma [TCC]) and advanced age. C

Cancer 1985 Sep 15;56(6):1293-9

Bladder carcinoma. Experience with radical and preoperative radiotherapy in 421 patients.

Yu. Four hundred twenty-one patients with bladder carcinoma were treated with radical intent between 1968 and 1981: 356 were treated with irradiation alone with megavoltage tumor doses of 60-66 Gy delivered over a period of 6 to 7 weeks. Actuarial 5- and 10-year survival was 66% and 58% for Stage A (58 patients), 42% and 35% for Stage B1 (62 patients), 35% and 28% for Stage B2 (120 patients), and 23% and 19% for Stage C (75 patients), respectively. Five-year survival after salvage cystectomy (47 patients) was 51% from the time of surgery, with 4 operative mortalities and a major complication rate of 30%. Early local recurrence may be salvaged in 50% to 60% of patients without a significant increase in mortality or major complications. Accordingly, a program of radical irradiation with salvage cystectomy may avoid loss of the bladder in 45% of patients in Stage B2-C-D1 without compromising overall survival.

Int J Radiat Oncol Biol Phys 1997 Nov 1;39(4):937-943

Invasive bladder cancer: treatment strategies using transurethral surgery, chemotherapy and radiation therapy with selection for bladder conservation.

Shipley The components of the combined treatment are usually transurethral resection of the bladder tumor (TURBT) followed by concurrent chemotherapy and radiation therapy. Following an induction course of therapy a histologic response is evaluated by cystoscopy and rebiopsy. Clinical "complete responders" (tumor site rebiopsy negative and urine cytology with no tumor cells present) continue with a consolidation course of concurrent chemotherapy and radiation. Those patients not achieving a clinical complete response are recommended to have an immediate cystectomy. Individually the local monotherapies of radiation, TURBT, or multidrug chemotherapy each achieve a local control rate of the primary tumor of from 20 to 40%. When these are combined, clinical complete response rates of from 65 to 80% can be achieved. Seventy-five to 85% of the clinical complete responders will remain with bladders free of recurrence of an invasive tumor. CONCLUSIONS: Bladder conservation trials using combined modality treatment approaches with selection for organ conservation by response of the tumor to initial treatment report overall 5-year survival rates of approximately 50%, and a 40-45% 5-year survival rate with the bladder intact. These modern multimodality bladder conservation approaches offer survival rates similar to radical cystectomy for patients of similar clinical stage and age. Bladder-conserving therapy should be offered to patients with invasive bladder carcinoma as a realistic alternative to radical cystectomy by experienced multimodality teams of urologic oncologists.

Urology 1995 Oct;46(4):499-504

Bladder-sparing multimodality treatment of muscle-invasive bladder cancer: a five-year follow-up.

Given Ninety-four patients with invasive transitional cell carcinoma of the bladder were treated by transurethral resection followed by 2 or 3 cycles of cisplatin-based chemotherapy. Patients were then treated with 6480 cGy of radiation in 49 patients, segmental cystectomy in 8, or surveillance only in 7. Patients who failed to respond to chemotherapy or radiation therapy, or who developed recurrent muscle-invasive disease in follow-up, underwent salvage cystectomy. Patients were then carefully followed for a median follow-up of more than 5 years. RESULTS. After initial therapy, 53 patients (56%) were alive with their bladder preserved. Thirty of those 53 (57%) developed a local recurrence in follow-up. After a median follow-up of more than 5 years, the ultimate relapse-free survival is 49% (Stage T2, 84%; T3, 53%; and T4, 11%; P < 0.01). Of all patients enrolled, 53% had bladder preservation; however, of the currently surviving patients, 16 of 39 (41%) have their bladders intact (T2, 50%; T3, 37%; T4, 0%).

J Clin Oncol 1998 Apr;16(4):1601-12

Role of adjuvant chemotherapy in the treatment of invasive carcinoma of the urinary bladder.

Dimopoulos The standard treatment for patients with muscle-invasive carcinoma of the urinary bladder is radical cystectomy. While radical cystectomy cures many patients with this tumor, almost 50% of them will develop metastatic disease. Adjuvant chemotherapy has been proposed for these patients in an attempt to reduce the probability of relapse and to improve survival. To assess whether adjuvant chemotherapy does benefit patients with muscle-invasive bladder cancer, we reviewed all phase II and III studies published in the English literature over the last 20 years. Several comparative, nonrandomized studies have indicated that adjuvant chemotherapy may prolong disease-free survival. Four randomized studies have been conducted and all had a suboptimal patient accrual. Three studies used a cisplatin-containing combination chemotherapy and included primarily patients with non-organ-confined transitional-cell carcinoma (TCC) of the bladder. All three studies indicated that adjuvant chemotherapy improved disease-free survival and two of them also showed improvement in event-free survival and overall survival, respectively. CONCLUSION: Published series have been unable to establish an undisputed benefit of adjuvant chemotherapy over radical cystectomy alone for muscle-invasive bladder cancer. The interpretation of the available data is compromised by several methodologic and statistical problems. Thus, adjuvant chemotherapy cannot be considered as a standard treatment for all patients with muscle-invasive carcinoma of the bladder. Well-designed prospective randomized studies are needed to clarify the role of adjuvant chemotherapy in this disease. However, outside a protocol setting, there is some evidence that patients with extravesical disease or with lymph node involvement may benefit from adjuvant treatment with cisplatin-based combination chemotherapy. No data support such an approach for patients with muscle-invasive but organ-confined bladder cancer.